The importance of enantiomerically pure compounds is a result of the enantiomeric selectivity of biology. Because biology is based on a particular enantiomer, L-amino acids, enantiomeric recognition is an inherent component of biological processes. A prototypical example of the enantiomeric selectivity is the case history of thalidomide. Thalidomide was a widely prescribed drug that was eventually removed from the market because of unforeseen side effects. Administered as a racemic mixture, the R-isomer is a sleep aid whereas the S-isomer is a potent teratogen. Thalidomide is not unique in having only one enantiomer of optically active compound that exhibits the desired pharmacological effect. However, because of the difficulties in synthesizing enantiomerically pure compounds, racemic mixtures are often used.
A relatively new and promising approach to enantioselective synthesis, where the chiral product is enriched in either enantiomer, is the use of optically active transition metal compounds as catalysts. Enantioselective catalysis in general hinges upon the ability to minimize the energy barrier (.DELTA..DELTA.G.dagger-dbl.) of the desired enantiomer product relative to the other. Small energy differences translates into relatively large differences in enantiomeric excess. For example, a 1.3 kcal/mole difference in transition state energies results in an enantiomeric excess of 80%.
Enantiomeric excess ("e.e.") is the enrichment of one enantiomer over the other from the expected value. For example, if the optically active product contains equal amounts of enantiomers, then the enantiomeric excess is 0. If the ratio is 70:30, then the enantiomeric excess is 40%, and if the ratio is 90:10, then the enantiomeric excess is 80% and so on.
Transition metals are good candidates for enantioselective catalysis because of their ability to mediate a wide variety of bond-forming and bond-breaking processes. Because transition metals do not display the necessary specificity, the conjunctive use of chiral ligands or auxiliaries is essential for enantioselective catalysis. Coordinated to the metal, the metal-ligand complex binds to the prochiral precursor and in so doing induces the formation of one enantiomer over the other. Because both sterics and electronics are readily modified, phosphines are often preferred. As a result, a large number of chiral phosphine ligands have been prepared. However, only a few have gained popular use probably because of difficulties in synthesis or inadequate enantiomeric excesses or a combination of both.
One area where enantiomerically pure compounds are useful is where an enantiomerically pure vinylglycinol (or vinylglycine) is used as a synthetic building block for biologically important targets, such as various antibiotic enzyme inhibitors, calmodulin inhibitors, and others. EP 529,601, published Mar. 3, 1993, inventors Fuelling and Kretzschmar is an example of optically active vinylglycine compounds, useful as enzyme inhibitors, antibacterials, and cytostatics. These optically active vinylglycines are produced by enzymatically resolving racemic vinylglycine; however, a simple asymmetric synthesis that would provide access to both enantiomers is most desirable.
At present, the most effective synthesis of vinylglycine has begun with amino acids, which restricts ready availability to the L-enantiomer. A simple asymmetric synthesis providing access to each enantiomer, as desired, would be quite useful.